PROJECT SUMMARY/ABSTRACT The developing visual cortex is remarkably plastic, capable of exhibiting a long-term modification of its neuronal responses to adapt to the external environment. However, this experience-dependent plasticity becomes much less prominent in the adult animal, responsible for reduced learning ability and incomplete recovery from brain injury. Therefore, it is critical to identify ways to enhance adult plasticity and elucidate its underlying neural mechanism. Recent works have demonstrated that running is effective in enhancing adult brain functions and visual plasticity in animals and human beings. Therefore, the proposed research aims to dissect the underlying circuit to uncover the principle governing brain plasticity and provide a mechanistic understanding for potential therapeutic intervention to promote rehabilitation and visual perceptual learning. I will characterize the intracortical circuit and subcortical neuromodulatory system involved in cortical plasticity, with novel and multidisciplinary approaches including state-of-the-art imaging techniques, optogenetics, and electrophysiology. In the mentored phase of the award, the proposed study will focus on local inhibitory circuit that contributes to the enhanced visual responsiveness during locomotion-dependent visual plasticity. Taking advantage of transgenetic mouse models and two-photon calcium imaging, I will measure the activity patterns in different types of inhibitory neurons, especially the less studied VIP and SST interneurons, at single-cell resolution to track their longitudinal changes during visual plasticity. I will also learn to utilize optogenetics, together with patch clamping, to determine how specific inhibitory inputs will contribute to visual enhancement in a subpopulation of excitatory neurons. In the independent stage of the award, I hope to lead a research team to pinpoint the neuromodulatory systems that play an essential role in driving plasticity. With viral tracing and deep-brain imaging, I aim to identify subcortical projecting pathways that convey locomotion-related information. I will combine in vivo optogenetics and high-density electrophysiology recording to study how neuromodulatory systems, particularly the long-questioned serotonin, affect cortical processing and leads to cortical plasticity. In the long term, I hope to understand how interconnected brain circuits integrate to modulate visual activity and plasticity, the fundamental basis for perceptual learning and rehabilitation in normal and pathological conditions. Dr. Stryker is a world-prominent expert in visual plasticity and a reputed mentor for foresting and supporting young scientists. Together with Dr. Sohal, the two labs at UCSF are an ideal environment for the proposed projects, which will provide me with abundant resources, substantial technical supports, and invaluable intellectual insights to ensure the successful completion of the research and career development training for transitioning into a potent independent researcher.